Alkylidenedithiobisphenols

ABSTRACT

Compounds having the general formula:   where R is an alkyl radical substituted by a radical selected from the class consisting of alkoxy, carbonyl and ester radicals. The compounds are useful for reducing blood cholesterol in warmblooded animals.

United States Patent 1191 Neuworth 1 Sept. 16, 1975 ALKYLIDENEDITHIOBISPHENOLS [75] Inventor: Martin B. Neuworth, Trumbull.

Conn.

[73] Assignee: Continental Oil Company, Ponea C ity, Okla.

[22] Filed: Nov. 20, 1974 [2]] Appl. No.: 525,331

Related US. Application Data [52] US. Cl. 260/609 F [51 Int. Cl. CO7C 149/36 [58] Field of Search 260/609 F {561 References Cited UNITED STATES PATENTS 3.786.100 l/l974 Neuworth 260/609 F Primary Iimminw-Elbert L. Roberts Axsislun! E.\umiIwi'D. R. Phillips Attorney, Agem. m1 FirmCortlan R. Sehupbach 5 7 ABSTRACT Compounds having the general formula:

where R is an alkyl radical substituted by a radical selected from the class consisting of alkoxy. carbonyl and ester radicals. The compounds are useful for re' dueing blood cholesterol in warm-blooded animals.

2 Claims. No Drawings The mercaptophenol and the appropriate carbonyl ALKYLIDENEDITHIOBISPHENOLS compound are preferably dissolved in an inert organic CROSS REFERENCE To RELATED APPLICATION solvent to provide a homogeneous reaction mixture. At

l least a stoichiometric amount of the carbonyl com- Thls a dlvlslon apPllcatlon N9- pound is used. The catalyst is a strong acid catalyst, for l M 1973* whlch tum was dwlslon of example hydrochloric acid, sulfuric acid, perchloric Pllcanon 206,929 l 197l PP acid, and strong acid cationic exchange resins. The re- U.S. Pat. No. 3,786,100), WhlCh m tum W213 u dwlslon action is mildly exothermic initially; external heating is of appllcatlon set 835,81], filsd f then required to maintain the reaction temperature, (now abandoned) Whlch m mm was a commuatlon m 10 generally between 50 and 100C. Reaction times of part of applications Ser. Nos. 637,622, 637,649 and to 6 hours are generally required all filed May l L 1967 (all now abandned)- The following examples illustrate the compounds of BACKGROUND OF THE INVENTION this invention. In each example, the chemical name and structural formula of the compound are first given. The F of F lnventlon identity of the compound produced in each example Thls mvemlon relates to a new and useful group M was established by conventional methods of analysis. sulfurcontaining bisphenols.

2. Description of the Prior Art EXAMPLE 1 US. Pat. Nos. 2,278,224 and 2,472,318 describe Preparation of compounds defined y the formula DRXR'XRD, 2,4-Pentanedione:2,2-bis(3,5-di-t-butyl-4-hydroxvwhich R is an aryl or alkyl aryl, or a substituted aryl or phenyl )mercapml alkyl aryl group, is a sulfur, oxygen or tellurium, but preferably a sulfur group, R is an alkyl or substituted H (H. H alkyl group and D is an inhibitor group taken from the U class of hydroxy, amino, sulfide, disulfide, or polysul- H0 Swims OH fide groups.

SUMMARY OF THE INVENTION i (,H,, I I(,H,, The novel chemical compounds of the present invention possess the property of lowering the cholesterol content of the blood of warm-blooded animals. They have the following general formula:

A SOO-milliliter flask (stirrer, thermometer, condenser) was charged with 23.8 grams of 2,6-di-tbutyltC,H,, CH, i c,H,,

I 4-mercaptophenol (0.1 mole) and 5.0 grams of 2,4- HO S C S OH pentanedione (0.05 mole) in 150 milliliters of methano]. 8.6 Milliliters of l2N HCl was added, and the mix- R ture held at about 6()7(lC. for about 3 hours. The i c,H,, i-c,a,, v

product mixture was placed in a separatory tunnel to which 100 milliliters of hexane and 200 milliliters of where R is an alkyl radical substituted by a radical se- H O were added. The aqueous phase was drained. A lected from the l s on i ing f y. carbonyl and solid product was recovered from the hexane solution ester radicals. by partial stripping of the solvent. The solid was recrys- The compounds of the present invention are pretallized from 95% ethanol (USP). lt wei hed 15.6

pared as follows. The appropriate 4-mercaptophenol is grams, and had a melting point of l2613()C. reacted with the appropriate carbonyl compound in the 7 presence of a strong acid catalyst according to the fol- EXAMPLE lowing equation: Preparation of r-C,H,, t C.,H,, (H3 t t,H,,

O l I Acid 2H0 SH+R CCH HO s-(' s -()H Catalyst I z C,H,, tC.,H,, R t(',H,,

where R is an alkyl radical substituted by a radical se- 2,4-Pentanedione:-2,2-bis( 3,5di-t-butyl-4-hydroxylected from the class consisting of alkoxy, carbonyl and phenyl )mercaptal, 4,4-diethylacetal ester radicals, The appropriate 4-mercaptophenol may be prepared by any one of several known methods. For i (,H,, (H,, r-C,H., example, thiocyanation of the appropriate phenol, followed by reduction, is one ofsuch methods. For details, o g ()H see Organic Reactions: Vol. III, Chapter 6, by Roger I Adams et al.; also the article by Miiller et al., entitled Untersuchungen an schwefelhaltigen Aroylen mittels der Electronenresonanz in Liebigs Annalen (1961. Ed. 645, p. 79); and. finally, U.S. Pat. No. 3,129,262. (H

A 500-milliliter flask (stirrer. thermometer. con denser with H O scrubber. gas inlet) was charged with 47.6 grams of 2.6-di-t-butyl-4-mercaptophenol (0.2 mole) and 5.0 grams of pentanedione (0.05 mole) in 166 milliliters of anhydrous ethyl ether. The solution was saturated with dry gaseous HCl. and maintained at about 80C. for about minutes. The product was placed in a flask and stripped of most of the solvent under H O pump vacuum with moderate heating. A heavy oil precipitated. 70 Milliliters of benzene was added to the flask and the resultant solution was placed in a separatory funnel and washed with 100 milliliters of H 0. The organic phase was then washed with two l00milliliter portions of 57: caustic solution. The caustic fraction was drained oft. The benzene phase was stripped of benzene by a water aspirator vacuum. A viscous oil formed which was dissolved in milliliters of hexane and then cooled in a dry ice chest. A crystalline product was obtained which was filtered on chilled equipment; washed with very cold hexane; and dried in a vacuum desiccator. It weighed 8.8 grams and had a melting point of 96l05C. This was recrystallized from 20 milliliters of ethanol; filtered; washed with ethanol; and dried in a vacuum desiccator (38C.). lts weight was 5.2 grams and its melting point was l20122.5(.

EXAMPLE 3 Preparation of 2-()ctanone:bis( 3.5-ditbutyl-4-hydroxyphenyl )mercaptal A 500-milliliter flask (stirrer. thermometer. condenser with H O scrubber. gas inlet) was charged with 23.8 grams of 2.6-di-t-butyl-4-mercaptophenol (0.1 mole) and 6.4 grams of Z-octanonc (0.05 mole) (the stoichiometric amount was used rather than the usual 1004 excess because of the difficulty of removing the unused ketone from the reaction mixture). in 150 milliliters olmethanol. The charge was heated to about 50C.. saturated with gaseous HCl. and held at 68C. for about 6 hours. A crystalline precipitate formed. The product mixture was filtered. washed with 100 milliliters 904 MeOH and air dried. 1t weighed 27.3 grams and had a melting point ol l26l27C. The yield was 9092.

EXAMPLE 4 Preparation of Acetoacetic Acid: 3 thio. ethyl ester;

bis( 3 .5-di-t-lmtyl-4-h droxyphenyl )ntercaptal no s s k o 14311., ('H. t (1H..

t'ootgi A 500-milli1iter flask (stirrer. thermometer. condenser. sparge tube, heating mantle) was charged with 47.6 grams of 3.5-di-t-butyl-4-hydroxythiophenol. 13.0 grams of ethyl aceto-acetate. and 150 millititers of anhydrous ethanol. The mixture was saturated with HCl gas. In 3 minutes the temperature rose from 19 to 74C; was held at reflux 2 hours; cooled; and diluted with 50 milliliters water to precipitate a heavy white paste. The paste was taken up in 100 milliliters benzene and 100 milliliters chloroform; washed to neutrality with three 100-milliliter portions of water; and dried over MgSO.,. The mixture was filtered and the benzene distilled off to yield a yellow viscous oil which crystallized upon standing. 25.4 Grams of product were recovered having a melting point of 104 to 108C. The yield was 43 percent.

EXAMPLE 5 Preparation of Z-Pentanone: 4-methyl. bis( 3.5di-t-butyl-4-hydroxyphenyl )mercaptal A 500-milliliter flask (stirrer. thermometer. condenser with H2O scrubber. gas inlet) was charged with 23.8 grams of 2.6-dit-butyl-4-mercaptophenol (0.1 mole) and 10.0 grams of methyl isobutyl ketone (0.1 mole) in 150 milliliters methanol. The solution was heated to about 50C. and saturated with HCl. The

mixture was held at a temperature near C. for about 6 hours. A crystalline solid had formed in the flask. The mixture was filtered; washed with 100 milliliters of methanol; and dried. 12.8 Grams of product were recovered having a melting point of l26130C. The yield was 44 percent.

EXAMPLE 6 Preparation of Pyruvic Acid: 2-thio. ethyl ester.

bis( 3 .5-di-t-butyl-4-hydroxyphenyl )mercaptal A 500-milliliter flask (stirrer. thermometer. sparge tube. condenser. heating mantle) was charged with 47.6 grams of 2.6di-t-butyl-4-mercaptophenol. 11.6 grams of ethyl pyruvate. and 150 milliliters of anhydrous denatured ethanol. The mixture was warmed to 35C to aid in dissolving the large chunks of mercaptohenol. Then. HCl gas was introduced (in 3 minutes. the temperature rose from 35"(". to 66C. and the solution was refluxed for 2 hours. The mixture was diluted with 200 milliliters of water and extracted with 100. then 50. milliliters of benzene. The combined ben- /ene phases were washed to neutrality with three milliliter portions of water. and dried over MgSO The mixture was filtered and stripped of benzene to yield a yellow solid precipitate. 33.9 Grams of white solid were recovered which had a melting point of 1 17 to l 18C.

The compounds of the present invention are useful for reducing the level of cholesterol in the blood of warm-blooded animals. They may be employed directly in suitable dosage, or as the active ingredient in a feed composition, or with suitable nontoxic carriers. Good results are obtained with dosages of from to 600 milligrams of active compound per kilogram of body weight of the recipient to provide a total intake of up to 3000 mg/kg per 24 hours.

The following table tabulates the percent reduction of cholesterol in the blood of rodents effected by the use of compounds of this invention. The compound was added to commercial rodent chow at a level of 0.125% by weight, and the mice were allowed to feed ad libitum for two weeks. At the end of this period, serum cholesterol determinations were performed on all the mice.

TABLE I Percent Cholesterol Reduction t3,S'di-bhutyl-4-hydroxyphenyl )-mercaptal The percent reductions in cholesterol content set forth in the foregoing Table l were calculated from statistically significant data. The general procedure was as follows:

Separate portions of balanced rodent mash were mixed together with each test compound to prepare a series of separate compositions each containing 0125 percent by weight of one test compound. Separate groups of male mice of the same origin and past history were fed for 2 weeks on separate diets consisting of one of the above-described compositions. Based on observations of average consumption of the composition and the concentration of the test compound, each mouse received an estimated oral dosage of about 250 milligrams of test compound per kilogram of animal body weight per day. A separate group of similar male mice was fed for 2 weeks on a diet consisting of an identical rodent mash which contained no test compound to serve as a check. At the end of the 2-week period, the mice in each group were anesthetized with ether and exsanguinated.

Serum cholesterol levels were determined for each mouse by taking a 0.05 milliliter aliquot of serum from each mouse and adding to the aliquot 3 milliliters of a 0.08 percent solution of ferric chloride in pure acetic acid. The serum was mixed with the ferric chlorideacetic acid solution and the mixture was allowed to stand for 10 to 15 minutes to flocculate protein. The protein was precipitated by centrifugation and the clear supernatent fluid was transferred to a stoppered test tube. Two milliliters of sulfuric acid was added to the supernatant and mixed well The tubes were then left to stand exposed to air for 20 to 30 minutes. Serum cholesterol was determined by measuring the percent transmission at a wave length of 560 millimicrons in a spectrophotometer and comparing the percent transmission to that observed with solutions containing known amounts of cholesterol.

The average serum cholesterol level in milligrams of cholesterol per I00 milliliters of serum was calculated for each test group and for the check group. The percentage reduction in serum cholesterol was calculated by dividing the difference between the cholesterol levels in the test group and the check group by the cholesterol level in the check group and multiplying the quotient by 100.

According to the provisions of the patent statutes, 1 have explained the principle, preferred construction, and mode of operation of my invention and have illustrated and described what 1 now consider to represent its best embodiment. However, I desire to have it understood that, within the scope ofthe appended claims. the invention may be practiced otherwise than as specifically illustrated and described.

I claim:

1. 2,4-Pentanedione12,2-Bis-(3.5-di-t-butyl-4- hydroxyphenyl )-mercaptal-4,4-diethyl acetal.

2. 2-Octanone:Bis-( 3.5-di-t-butyl-4-hydroxyphenyl 

1. 2,4-PENTANEDIONE:2,2-BIS-(3,5-DI-T-BUTYL-4-HYDROXYPHENYL)-MERCAPTAL-4,4 -DIETHYL ACETAL.
 2. 2-Octanone:Bis-(3,5-di-t-butyl-4-hydroxyphenyl)-mercaptal. 